1. Field of the Invention
The present invention relates to a process for preparing organozinc halides (halogen-zinc compounds, Reformatsky reagents) from reactive halogen compounds and to their use in preparing keto, hydroxyl and amino compounds in carboxylic esters.
2. The Prior Art
The reaction of reactive halogen compounds, in particular of xcex1-halocarbonyl compounds, with electrophilic substrates, for example aldehydes, ketones, imines, nitriles, carboxylic anhydrides, carboxylic chlorides, lactones, orthoformates, formates, epoxides, azirines, aminals and nitrones, in the presence of zinc metal, is known as the Reformatsky reaction. This reaction produces important synthetic building blocks for preparing active pharmaceutical ingredients, scents and crop protecting agents.
The choice of the solvent and the activation of the zinc used or of the entire reaction mixture are of decisive importance for the achievement of good yields and high selectivities and therefore good product purities.
It is known that particularly useful solvents for the Reformatsky reaction include ethers such as diethyl ether, 1,4-dioxane, dimethoxymethane, dimethoxyethane and in particular tetrahydrofuran. In addition, further solvents which have proven useful include aromatic hydrocarbons or mixtures of the abovementioned ethers with aromatic hydrocarbons, the mixture of tetrahydrofuran with trimethyl borate, and the polar solvents acetonitrile, dimethylformamide, dimethyl-acetamide, dimethyl sulfoxide and hexamethyl-phosphoramide. A review on this subject is contained, for example, in A. Fxc3xcrstner, Synthesis 1989, pp. 571-590.
EP-A-562 343 discloses that the reaction of xcex1-bromocarboxylic esters with carbonyl compounds in the presence of zinc in the solvent methylene chloride proceeds with high yields.
The use of the solvents and solvent mixtures mentioned has the following disadvantages:
the water-miscible ethers 1,4-dioxane and tetrahydrofuran and also the water-miscible polar solvents acetonitrile, dimethylformamide, dimethylacetamide, dimethyl sulfoxide and hexamethylphosphoramide dissolve in the aqueous phase on aqueous workup to hydrolyze the zinc compounds and zinc salts formed.
Particularly when applied on the industrial scale, it is necessary, for economic reasons and to reduce the amounts of waste, and to recover the solvents used from the aqueous phase. This recovery may be done for example by extraction or distillation, which is, however, associated with considerable cost and inconvenience.
In addition, when the abovementioned water-miscible solvents are used in the hydrolysis of the reaction mixture, it is customarily necessary to use water-immiscible organic solvents such as ethyl acetate or methyl tert-butyl ether as cosolvents for better phase separation. These solvents have to be recovered and, before reuse, freed of impurities by distillation, which is likewise associated with high cost and inconvenience. When solvent mixtures are used for Reformatsky reactions, the recovery, separation and any purification of the individual solvents used generally entails even more considerable cost and inconvenience.
Furthermore, when diethyl ether, 1,4-dioxane, dimethoxymethane, dimethoxyethane and tetrahydrofuran are used as solvents for Reformatsky reactions, they tend to form explosive peroxides by autoxidation. This makes their use on the industrial scale dangerous, in particular on repeated use after recovery (danger of accumulation of the explosive components). Or it makes their use more difficult or possible only at great cost and inconvenience.
The use of methylene chloride as solvent, as disclosed by EP-A-562 343, or of other halogenated hydrocarbons as solvents is objectionable for environmental reasons. Accordingly it is to be avoided, on the industrial scale in particular. In addition, many of the abovementioned solvents are expensive which additionally compromises the economic viability of the reaction without recovery of the solvent used.
SU 472127 discloses the reaction of xcex1-bromoketones and zinc with nitrites in ethyl acetate as solvent for preparing xcex1-iminoketones. A mixture of bromoketone (reactive halogen compound) and nitrile (electrophilic substrate) is added to activated zinc, and the organozinc halide formed (Reformatsky reagent) reacts immediately with the substrate. For many substrates, the addition of a mixture of reactive halogen compound and electrophilic substrate described in SU 472127 is highly disadvantageous.
Certain substrates which have further functional groups, for example amino or epoxide functionalities, react as soon as they are combined with the reactive halogen compound (for example xcex1-haloester, xcex1-bromoketone). They form undesired by-products before the actual contact with the zinc takes place. For instance, those skilled in the art are familiar with the reaction of amines or epoxides with reactive halogen compounds, for example from X.-P. Gu, I. Ikeda, M. Okahara, Bull. Chem. Soc. Jpn., 1987, 60, pp. 397-398. The process described is accordingly unsuitable for such substrates.
It is an object of the present invention to provide a process which solves the problems known from the prior art.
The present invention provides a process for preparing organozinc halides in solvents, which comprises reacting a reactive halogen compound with zinc in one or more carboxylic esters.
In a preferred embodiment of the invention, the process according to the invention is used to prepare organozinc halides of the general formula (4)
HalZnxe2x80x94R3R4Cxe2x80x94(X)1xe2x80x94Yxe2x80x83xe2x80x83(4)
by reacting reactive halogen compounds of the general formula (2)
xe2x80x83Hal-R3R4Cxe2x80x94(X)1xe2x80x94Yxe2x80x83xe2x80x83(2)
with zinc, where
R1 and R2 are each hydrogen or an optionally halogen- or cyano-substituted C1-C30-hydrocarbon radical in which one or more nonadjacent methylene units may be replaced by xe2x80x94Oxe2x80x94, xe2x80x94COxe2x80x94, xe2x80x94COOxe2x80x94, xe2x80x94OCOxe2x80x94, or xe2x80x94OCOOxe2x80x94, xe2x80x94Sxe2x80x94 or xe2x80x94NRxxe2x80x94 groups and in which one or more methine units may be replaced by xe2x80x94Nxe2x95x90 or xe2x80x94Pxe2x95x90 groups,
R3, R4, R5, R6 and R7 are each hydrogen, halogen or an optionally halogen-substituted or cyano-substituted C1-C30-hydrocarbon radical in which one or more nonadjacent methylene units may be replaced by xe2x80x94Oxe2x80x94, xe2x80x94COxe2x80x94, xe2x80x94COOxe2x80x94, xe2x80x94OCOxe2x80x94, or xe2x80x94OCOOxe2x80x94, xe2x80x94Sxe2x80x94 or xe2x80x94NRxxe2x80x94 groups and in which one or more methine units may be replaced by xe2x80x94Nxe2x95x90 or xe2x80x94Pxe2x95x90 groups,
X is selected from 
l is an integer having the value 0 or 1,
Y is CN, (Cxe2x95x90O)xe2x80x94Z, (SO2)xe2x80x94Z, (Pxe2x95x90O) (xe2x80x94Z)2, R5Cxe2x95x90CR6R7, Cxe2x89xa1Cxe2x80x94R5 
or an aromatic radical in which one or more methine units in the ring may be replaced by xe2x80x94Nxe2x95x90 or xe2x80x94Pxe2x95x90 groups and which may carry the heteroatoms xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94 or xe2x80x94NHxe2x80x94 in the ring, where the aromatic ring is optionally halogen- or cyano-substituted or is substituted by C1-C30-hydrocarbon radicals in which one or more nonadjacent methylene units may be replaced by xe2x80x94Oxe2x80x94, xe2x80x94COxe2x80x94, xe2x80x94COOxe2x80x94, xe2x80x94OCOxe2x80x94, or xe2x80x94OCOOxe2x80x94, xe2x80x94Sxe2x80x94 or xe2x80x94NRxxe2x80x94 groups,
Z is an optionally halogen-substituted C1-C30-hydrocarbon radical in which one or more nonadjacent methylene units may be replaced by xe2x80x94Oxe2x80x94, xe2x80x94COxe2x80x94, xe2x80x94COOxe2x80x94, xe2x80x94OCOxe2x80x94, xe2x80x94OCOOxe2x80x94, xe2x80x94Sxe2x80x94 or xe2x80x94NRxxe2x80x94 groups and in which one or more methine units may be replaced by xe2x80x94Nxe2x95x90 or xe2x80x94Pxe2x95x90 groups, OH, OR1, OSi(R3)3, NHR1 or NR1R2,
Hal is chlorine, bromine or iodine,
Rx is hydrogen or an optionally halogen-substituted C1-C30-hydrocarbon radical in which one or more nonadjacent methylene units may be replaced by xe2x80x94Oxe2x80x94, xe2x80x94COxe2x80x94, xe2x80x94COOxe2x80x94, xe2x80x94OCOxe2x80x94, or xe2x80x94OCOOxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94NHxe2x80x94 or xe2x80x94Nxe2x80x94C1-C20-alkyl groups and in which one or more methine units may be replaced by xe2x80x94Nxe2x95x90 or xe2x80x94Pxe2x95x90 groups, and pairs of radicals selected from R1 and R2, R3 and R4, R4 and R5, R5 and R6, R6 and R7, R1 and R3, R1 and Y, R1 and Z, R3 and Y, R3 and Z, R5 and Y, R5 and Z, where Z may be a direct bond, may each be linked to each other.
The invention further provides the use for preparing keto, hydroxyl and amino compounds of organozinc halides obtained in a first step from a reactive halogen compound and zinc in one or more carboxylic esters, wherein the organozinc halide obtained is reacted in a second step with an electrophilic reaction partner and the reaction product of the second step is hydrolyzed in a third step.
Preference is given to using the process according to the invention for preparing keto, hydroxyl and amino compounds of the general formula (1)
R1(R2)kC(Wx)xe2x80x94R3R4Cxe2x80x94(X)1xe2x80x94Yxe2x80x83xe2x80x83(1)
wherein the electrophilic reaction partner used in the second step is an aldehyde, ketone or imine of the general formula (5a)
R1R2Cxe2x95x90Wxe2x80x83xe2x80x83(5a)
or an epoxide of the general formula (5b) 
or a nitrile of the general formula (5c)
R1Cxe2x89xa1Nxe2x80x83xe2x80x83(5c)
or a carboxylic halide of the general formula (5d)
R1(Cxe2x95x90O)-Halxe2x80x83xe2x80x83(5d)
where
Wx is OH, NHR1 or xe2x95x90O and
W is O or NR1,
k when Wx is OH and NHR1, should have the value 1 and, when Wx is xe2x95x90O, should have the value 0, and
the remaining radicals are defined above and in addition pairs of 2 radicals selected from R1 and R2, R3 and R4, R4 and R5, R5 and R6, R6 and R7, R1 and R3, R1 and Y, R1 and Z, R3 and Y, R3 and Z, R5 and Y, R5 and Z, Wx and Y and also Wx and Z, where Wx is Oxe2x80x94 or NR1xe2x80x94 and Z may be a direct bond, may each be linked to each other.
The invention further provides solutions of organozinc halides in carboxylic esters which are prepared by the process according to the invention.
It has surprisingly been found that carboxylic esters are on the one hand suitable solvents for preparing organozinc halides (Reformatsky reagents) from reactive halogen compounds and zinc.
Furthermore, carboxylic esters are also outstandingly suitable for further reactions of the halogen-zinc compounds with electrophilic substrates (Reformatsky reaction), in particular with aldehydes, ketones, imines, nitrites, carboxylic halides and epoxides, and also for the subsequent hydrolysis of the reaction products obtained in this way in a further reaction step.
In this way, keto, hydroxyl and amino compounds in particular can be prepared.
The use of carboxylic esters as solvents makes it possible to carry out the reaction on the industrial scale in particular without the addition of further solvents or cosolvents or the use of solvent mixtures. The reaction occurs with high yields and selectivities while at the same time allowing simple recovery of the solvent used. As a consequence the reaction occurs in an environmentally friendly and cost-effective manner, since the amounts of waste can be markedly reduced.
The Reformatsky reagents prepared by the process according to the invention in the form of organozinc halides dissolved in carboxylic esters are surprisingly stable as reactive organometallic intermediates over long periods even at relatively high temperatures. They may be reacted further immediately or not until a later time in subsequent reaction steps, in particular with electrophilic substrates.
The Reformatsky reagents prepared by the process according to the invention in the form of organozinc halides dissolved in carboxylic esters therefore constitute reaction-ready solutions. They are universally usable starting compounds for reactions with electrophiles, in particular for Reformatsky reactions.
The above-described process according to the invention allows keto, hydroxyl and amino compounds of the general formula (1) to be obtained in very high yields of up to  greater than 90% and very high purities in a simple manner and at simultaneously very good space-time yields.
The process according to the invention is simple to perform, particularly on the industrial scale. This is because the reaction may be carried out in the commercially obtainable carboxylic esters of the general formula (3) as solvents without pretreatment of these solvents, for example distillation or drying, being necessary.
The subsequent reaction steps in the form of further reactions with electrophiles, in particular of Reformatsky reactions, do not require the addition of a further solvent. For example, it is not necessary to add a cosolvent for better phase separation in the workup, either for carrying out the reaction or for the workup. Since no solvent mixtures have to be added, the solvents used can be recovered very simply. The carboxylic esters of the general formula (3) which are preferably used are only slightly or very sparingly soluble in water. Therefore they can be easily and efficiently recovered, for example in the product isolation, which makes the reaction very economical. For example, when ethyl acetate, isopropyl acetate or butyl acetate are used as the solvent of the general formula (3), they can be recovered in very high yields when the products prepared are isolated by distillation.
The processes according to the invention additionally facilitate the replacement of halogenated hydrocarbons and ethers prone to peroxide formation by carboxylic esters of the general formula (3) as the solvent. This not only makes the processes according to the invention more environmentally friendly but also markedly reduces the danger potential.
Furthermore, in many cases, the product yield and quality of the keto, hydroxyl and amino compounds of the general formula (1) prepared according to the process variant according to the invention are improved compared to the existing variants described in the literature. The use of carboxylic esters of the general formula (3) is particularly advantageous for the progress of the reaction, the product yields and purities and the elimination of secondary reactions.
In addition, the processes according to the invention may be performed in most cases with a slight excess of zinc and reactive halogen compound of the general formula (2), based on the electrophilic reaction partner. This results in many cases in higher product yields and qualities than in existing variants using the previously known solvents mentioned. This makes the process according to the invention particularly economical.
Furthermore, the process according to the invention advantageously also makes it possible to react electrophilic substrates which have nucleophilic functional groups (for example amino groups) or nucleophilic properties (for example epoxides). They react as soon as they are combined with the reactive halogen compound forming undesired by-products even before contact with the zinc. However, the organozinc halide prepared in the first reaction step of the process according to the invention from reactive halogen compound and zinc is reacted in the second reaction step with the substrates (for example epoxides or substrates having amino groups) in high yields and high purities to be changed into the desired products without forming undesired by-products (See Example 5).
In addition, it is possible for the organozinc halides prepared in the first step of the process according to the invention to be reacted with the electrophiles in a second step under mild conditions at low temperature to obtain high yields and in particular high purities. This allows electrophilic reaction partners, for example epoxides, which are particularly sensitive and unstable at relatively high temperatures as are required for preparing the organozinc halides in the first step to be reacted with high yields and product purities. In contrast, when a mixture of bromoacetic ester and styrene oxide is reacted with zinc at an elevated temperature of 55-65xc2x0 C., as described in SU 472127, the drastic reaction conditions result in decomposition of the reaction mixture to form undesired by-products (See Comparative Example 7).
Also, the organozinc halides prepared in the first reaction step can initially be stored stably or intermediately stored before reaction with the electrophilic reaction partner. This is advantageous in particular in industrial implementation, since this allows industrial production processes to be configured optimally in terms of time, personnel and capacity, and to be run in parallel. This which makes the process according to the invention particularly economical in particular when carried out on the industrial scale.
The C1-C30-hydrocarbon radicals for R1, R2, R3, R4, RS and Z are preferably linear, branched or cyclic C1-C20-alkyl, C3-C20-alkoxycarbonylalkyl, C2-C20-alkenyl, C5-C20-acetalalkenyl or C3-C20-alkoxycarbonylalkyl radicals, each of which may be substituted by F, Cl, Br, I, CN or C1-C8-alkoxy radicals; aryl, aralkyl, alkaryl, aralkenyl or alkenylaryl radicals in which one or more methine units may be replaced by xe2x80x94Nxe2x95x90 or xe2x80x94Pxe2x95x90 groups and methylene units by xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94 or xe2x80x94NHxe2x80x94, each of which may be substituted by F, Cl, Br, I, CN, C1-C10-alkoxy radicals or C1-C20-alkylamino radicals and, on the ring, by C1-C10-alkyl radicals and may carry the heteroatoms xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94 or xe2x80x94NHxe2x80x94 in the ring.
The radicals R1 and R2, R3 and R4, R4 and R5, R5 and R6, R6 and R7, R1 and R3, R3 and Y, R3 and Z, R3 and Y, R3 and Z, R5 and Y, R5 and Z, Wx and Y, and Wx and Z, where Wx is Oxe2x80x94 or NR1xe2x80x94 and Z may be a direct bond, may be linked to each other. The radicals R1 and R3, R1 and Y, R1 and Z, Wx and Y, and Wx and Z, where Wx is Oxe2x80x94 or NR1xe2x80x94 and Z may be a direct bond, may be linked to each other by intramolecular reaction.
The halogen radicals R3, R4, R5, R6 and R7 are preferably F and Cl.
In particular, 1 has the value 0.
The reactive halogen compounds of the general formula (2) used are preferably bromine compounds, where Hal in the general formula (2) is bromine. Preference is given to reactive halogen compounds of the general formula (2) in which Y is (Cxe2x95x90O)xe2x80x94Z. Preference is further given to reactive halogen compounds of the general formula (2) in which Z is OR1. In particular, preference is given to xcex1-bromocarboxylic esters as the reactive halogen compounds of the general formula (2).
In the use according to the invention of organozinc halides in a process for preparing keto, hydroxyl and amino compounds, preference is given to initially charging the zinc in the carboxylic ester of the general formula (3) in a first step and then adding the reactive halogen compounds of the general formula (2), optionally dissolved in a solvent.
In a second step, suitable electrophilic substrates, preferably aldehydes, ketones, imines, epoxides, nitrites and carboxylic halides of the general formulae (5a) to (5d), optionally dissolved in a solvent, are added to the solution of the organozinc halides of the general formula (4) obtained in the first step.
Preference is likewise given to adding the solution of the organozinc halides of the general formula (4) obtained in the first step to suitable electrophilic substrates. These substrates are preferably aldehydes, ketones, imines, epoxides, nitriles and carboxylic halides of the general formulae (5a) to (5d), optionally dissolved in a solvent, in a second step.
A. Fxc3xcrstner, Synthesis 1989, pp. 571-590 and K. Nxc3xctzel in Houben-Weyl, Methoden der organischen Chemie, 4th edition, Vol. XIII/2a, Stuttgart 1973, pp. 828-832 disclose that xcex1-bromozinc esters (Reformatsky reagents) of the general formula (4) can react with certain reactive carboxylic esters, viz. cyclic carboxylic esters (lactones), formic esters, orthoformic esters and benzoic esters. Reactive carboxylic esters other than those mentioned above are not reactive toward xcex1-bromozinc esters. In exceptional cases, a reaction does take place either when coordinating or polar solvents (for example 1,4-dioxane or dimethyl sulfoxide) are used or when the reaction times are long and temperatures are high at the same time.
Surprisingly, the organozinc halides (Reformatsky reagents) of the general formula (4) prepared by the process according to the invention are sufficiently stable and storable (see examples) in the carboxylic esters of the general formula (3). These esters can be used as solvent in the process according to the invention even at elevated temperatures. They can be converted directly to keto, hydroxyl or amino compounds in subsequent reaction steps by reaction with electrophilic substrates and hydrolysis, which would not have been expected on the basis of the teachings of the prior art.
During the preparation of the organozinc halides by the process according to the invention, the temperature of the exothermic reaction is generally maintained at a predetermined value, if necessary by cooling. The upper temperature limit may be defined by the boiling point of the solvent of the general formula (3) used, for example ethyl acetate (b.p.: 77xc2x0 C.) or isopropyl acetate (b.p.: 87-89xc2x0 C.). In the case of higher-boiling solvents of the general formula (3), for example n-butyl acetate (b.p.: 124-126xc2x0 C.), preference is given to controlling the temperature of the reaction by cooling. Preference is given to carrying out the reaction at temperatures of from xe2x88x9220 to +150xc2x0 C., more preferably from 20 to 110xc2x0 C., in particular from 40 to 90xc2x0 C.
Zinc is generally used in the form of sheets, ribbon, turnings, powder or dust, or in the form of zinc wool. The presence of other metals such as copper, silver or mercury is not necessary. In particular, zinc is used in the form of commercially obtainable, commercially customary zinc powder or zinc dust. Preference is given to zinc of high purity of at least 99.995%, greater preference to zinc dust which is obtained from zinc having a purity of at least 99.995%.
To achieve high product yields, it has generally proven advantageous to activate the zinc before addition of the reactive halogen compound of the general formula (2). For zinc activation, existing methods which are customarily used and mentioned, for example, in the review of A Fxc3xcrstner, Synthesis 1989, pp. 571-590, are suitable. Particularly advantageous methods have proven to be washing of the zinc with acid, activation by iodine, as described in EP-A-562 343, and the activation by trimethylchlorosilane. Particular preference is given to the activation by trimethylchlorosilane due to its ease of performance and the increased yields, product purities and selectivities, and also the suppression of secondary reactions. G. Picotin, P. Miginiac, J. Org. Chem. 1987, 52, p. 4796 disclose the activation of zinc by trimethylchlorosilane in the solvent diethyl ether.
To activate zinc using trimethylchlorosilane, the zinc is initially charged in the carboxylic ester of the general formula (3), then trimethylchlorosilane is added and the mixture is heated for from 10 min to 2 h, preferably from 10 to 45 min, at temperatures of from 30 to 150xc2x0 C., in particular from 40 to 120xc2x0 C., more preferably from 50 to 90xc2x0 C. It has proven advantageous to react the zinc with trimethylchlorosilane in a molar ratio of 1:(0.005 to 0.5), in particular 1:(0.03 to 0.3) in the carboxylic ester of the general formula (3) with heating to the desired temperature.
For activation of the reaction mixture, it is also possible to add additives such as compounds of copper, chromium, manganese, cobalt, bismuth, samarium, scandium, indium, titanium, cerium, tellurium, tin, lead, antimony, germanium, aluminum, magnesium, palladium, nickel and mercury or optionally mixtures thereof.
Carboxylic esters which may be used for the processes according to the invention are preferably carboxylic esters of the general formula (3)
R8xe2x80x94((O(CH2)m)nxe2x80x94COOxe2x80x94((CH2)oxe2x80x94COO)pxe2x80x94((CH2)qxe2x80x94O9xe2x80x83xe2x80x83(3)
where
R8 and R9 are each a C1-C30-hydrocarbon radical in which one or more nonadjacent methylene units may be replaced by xe2x80x94Oxe2x80x94 groups, and
m, n, o, p, q and r are integers having values of from 0 to 6.
Preference is given in particular to those carboxylic esters of the general formula (3) in which Re and R9 are preferably straight-chain, branched or cyclic C1-C10-alkyl, C6-C10-aralkyl, C2-C10-alkoxyalkyl radicals or C5-C10-aryl radicals. In particular, R8 and R9 are each straight-chain or branched C1-C8-alkyl radicals.
m, n, o, p, q and r are preferably integers having values of 0, 1, 2 or 3. In particular, n and p and r have the value 0.
Particularly preferred carboxylic esters of the general formula (3) are in particular methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, n-hexyl, n-pentyl and i-pentyl esters of acetic acid, of propionic acid and of butyric acid and (C6-C14) alkyl acetate mixtures. The esters and the (C6-C14) alkyl acetate ester mixtures may be recovered in very high yield when the products prepared are isolated and reused. When the inexpensive methyl acetate is used as the solvent of the general formula (3), recovery may be dispensed with.
After the completed reaction and the preparation according to the invention of the organozinc halides in the first step, the reaction mixture is admixed in the second step, customarily at temperatures of from xe2x88x92100 to +200xc2x0 C., more preferably from xe2x88x9250 to +130xc2x0 C., in particular from xe2x88x9230 to +80xc2x0 C., with electrophilic substrates while preferably maintaining the temperature of the exothermic reaction at a predetermined value, optionally by cooling. The upper temperature limit may be defined by the boiling point of the solvent of the general formula (3) used, for example ethyl acetate (b.p.: 77xc2x0 C.). Preference is given to controlling the temperature of the reaction by cooling.
Alternatively, the reaction mixture may also be added to the electrophilic substrates. After cooling of the reaction mixture at temperatures of from xe2x88x9220 to +30xc2x0 C., the organozinc halides of the general formula (4) prepared in the first step may also initially be stored stably and reacted at a later time with electrophilic reaction partners.
After the end of the addition of all reacting components in the second step, preference is given to allowing the reaction to continue for a further from 5 min to 24 h, more preferably from 5 min to 12 h, in particular from 5 min to 8 h, in order to complete the reaction. At reaction temperatures of from 20 to 90xc2x0 C., the post-reaction time is preferably from 5 min to 2 h, in particular from 5 min to 30 min.
Excess zinc metal may be removed by filtration. It is also possible to dissolve excess zinc in the acid used in the third step for hydrolysis of the reaction mixture.
It has proven useful to react the zinc with the reactive halogen compound of the general formula (2) and the electrophilic substrate of the general formulae (5a) to (5d) in a molar ratio of (1 to 3):(1 to 2):1, in particular (1.1 to 1.7):(1 to 1.3):1 in the carboxylic ester of the general formula (3) as solvent.
Furthermore, the processes according to the invention prove to be advantageous compared to existing process variants. This is because in many cases, in particular at reaction temperatures of from 20 to 80xc2x0 C., the post-reaction time of from 5 to 30 min is distinctly shortened. This in particular on the industrial scale, allows very good space-time yields and accordingly very good economic viability to be achieved. Very short post-reaction times result in particular from activation of the reaction mixture or of the zinc using trialkylchlorosilane in the carboxylic ester of the general formula (3) as solvent.
After the completed reaction in the second step, the reaction mixture is hydrolyzed in the third step, customarily at temperatures of from xe2x88x9280 to +90xc2x0 C., more preferably from xe2x88x9250 to +50xc2x0 C., in particular from xe2x88x9230 to +30xc2x0 C., by adding an aqueous acid or base, and zinc compounds and zinc salts which have formed are dissolved. Alternatively, the reaction mixture may also be added to an aqueous acid or base.
Preferred bases for the hydrolysis are ammonia and organic amines, such as trialkylamines and alkanolamines.
Preferred acids for the hydrolysis are Brxc3x6nsted acids, in particular strong acids such as boric acid, tetrafluoroboric acid, nitric acid, nitrous acid, phosphoric acid, phosphorous acid, hypophosphorous acid, sulfuric acid, sulfurous acid, peroxosulfuric acid, hydrochloric acid, hydrofluoric acid, hydroiodic acid, hydrobromic acid, perchloric acid, hexafluorophosphoric acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, trifluoromethanesulfonic acid and carboxylic acids such as chloroacetic acid, trichloroacetic acid, acetic acid, acrylic acid, benzoic acid, trifluoroacetic acid, citric acid, crotonic acid, formic acid, fumaric acid, maleic acid, malonic acid, gallic acid, itaconic acid, lactic acid, tartaric acid, oxalic acid, phthalic acid and succinic acid.
In particular, ammonia, hydrochloric acid, sulfuric acid, citric acid or acetic acid, preferably ammonia, hydrochloric acid or sulfuric acid, are used. The acid or base may be used in concentrated form or in the form of a dilute aqueous solution.
The products of the general formula (1) prepared may be isolated by known, customarily used methods such as extraction, distillation, crystallization or by means of chromatographic methods. In most cases, the crude product obtained after removal of the solvent is of very high purity or sufficient purity and may be used immediately in subsequent reactions and conversions, in particular ester hydrolyses.
The pressure range of the reaction is uncritical and may be varied within wide limits. The pressure is customarily from 0.01 to 20 bar, and preference is given to carrying out the reaction under atmospheric pressure.
Preference is given to carrying out the reaction under inertization with protective gas such as nitrogen or argon. The reaction may be carried out continuously or batchwise, preferably batchwise.
All of the abovementioned symbols of the abovementioned formulae are each defined independently of one another.